Current measures are not sufficient: an interview-based qualitative assessment of quality of life in cutaneous T-cell lymphoma.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) negatively impacts quality of life (QoL), but existing QoL questionnaires may not comprehensively reflect patients' experience. OBJECTIVES: To identify the aspects of QoL that are most meaningful to patients with CTCL and to evaluate existing QoL instruments in this context. METHODS: Semistructured interviews were conducted between May and June 2019 using purposive sampling of patients with CTCL. Data were analysed by an inductive thematic approach using Dedoose Version 8.0.35. RESULTS: One-on-one interviews lasting a median of 43 min were completed by 18 patients [median age 62 years (interquartile range 52-70); 39% advanced-stage (IIB-IV)]. Itch was the most common clinical symptom reported (16 of 18 patients), followed by pain (12 of 18), skin breaks (11 of 18) and skin flaking (10 of 18). Eleven patients reported that their symptoms interfered with sleep, which impacted daily functioning. Patients also noted a lack of understanding of the disease in the community and felt uncertain (12 of 18), depressed (11 of 18), suicidal (four of 18) and hopeless (nine of 18). Nearly all patients (17 of 18) reported a sense of 'otherness' (not feeling 'normal' or 'like themselves'), and most patients (16 of 18) specifically mentioned concern about their physical appearance. Patients also noted substantial treatment burden. Salient patient concerns, including individual clinical symptoms, concern about appearance and problems with sleep, were not adequately or consistently represented in generic, skin-specific or CTCL-specific QoL measures. CONCLUSIONS: Incorporating the concerns and priorities that distinguish patients with CTCL from other patient populations will be of paramount importance in developing a comprehensive CTCL-specific measure of QoL that adequately captures patients' experience.

Health-related quality of life and economic implications of cutaneous T-cell lymphoma.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) has been associated with considerable physical, psychological and financial burden. However, its impact on health-related quality of life (QoL) and economic costs are not well studied. OBJECTIVES: To measure the QoL impact and financial burden of CTCL. METHODS: A cross-sectional survey of 67 patients with CTCL was conducted using the Ontario Health Utilities Index Mark 3 (HUI3) questionnaire. Normative population data (n = 3310) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Economic cost was estimated using quality-adjusted life-year (QALY) loss derived from HUI3 scores. RESULTS: Patients with CTCL had significantly lower aggregate HUI3 scores than the general population (0·68 vs. 0·87, P < 0·001). Multivariable regression analysis adjusting for demographics and comorbidities showed CTCL was associated with significantly poorer performance overall (-0·13, 95% CI -0·21 to -0·06, P < 0·001) and in domains of speech (-0·03, 95% CI -0·05 to -0·01, P = 0·01), ambulation (-0·04, 95% CI -0·08 to 0·00, P = 0·03), emotion (-0·07, 95% CI -0·12 to -0·02, P = 0·01), and pain (-0·07, 95% CI -0·13 to -0·01, P = 0·03). These health utility decrements yielded an average loss of 1·48 QALYs per patient. Using a $50 000 per QALY willingness-to-pay threshold, CTCL was associated with an individual lifetime burden of $73 889 and U.S. societal burden of $2·86 billion. CONCLUSIONS: These findings suggest CTCL has a pervasive impact on QoL, comparable with debilitating conditions such as end-stage renal disease. The substantial economic burden of CTCL underscores the potential societal benefit of prompt diagnosis and effective management. What's already known about this topic? Cutaneous T-cell lymphoma is associated with physical, psychological and financial burden. What does this study add? The overall quality-of-life impact of cutaneous T-cell lymphoma has not previously been measured using a generic health utility instrument. In this study, we compare the overall quality-of-life burden of patients with cutaneous T-cell lymphoma with that of other populations and calculate the economic burden of the disease.

Clinical severity measures and quality-of-life burden in patients with mycosis fungoides and Sézary syndrome: comparison of generic and dermatology-specific instruments.

BACKGROUND: Given the severe symptom burden and chronic nature of mycosis fungoides (MF) and Sézary syndrome (SS), effective assessment of quality of life (QoL) is essential to guiding patient-centred care in this population. In this study, we aim to provide a comprehensive assessment of QoL in early- and advanced-stage MF/SS and to assess the correlation of traditional measures of clinical severity with QoL measures. METHODS: Between July 2017 and April 2019, outpatients at an academic medical centre with either MF/SS (n = 115) or general dermatology concerns (n = 115) completed generic and dermatology-specific QoL instruments [Health Utilities Index Mark 3 (HUI3), RAND 36-Item Short-Form Health Survey (SF-36), Skindex-29, visual analogue scale for itch (VAS itch) and 5-D pruritus scale]. The mean scores of MF/SS patients were compared to that of controls using multivariable regression models adjusted for demographics and medical comorbidities. Cluster analysis of the QoL instruments and clinical severity measures (e.g. stage and body-surface-area involvement) was performed. RESULTS: Patients with MF/SS scored significantly worse than controls on all QoL instruments used, with advanced-stage (IIB-IVB) disease having the worst QoL impairment. Early-stage (IA-IIA) and advanced-stage MF/SS patients had significantly reduced overall health status (HUI3; P < 0.05), with largest decrements in social functioning and usual role functioning due to physical and emotional health (SF-36; all P < 0.05). MF/SS had significantly worse skin-specific impairment than controls, with advanced-stage disease reporting the most severe skin-specific burden (Skindex-29, P < 0.05). Clinical severity measures had a weak correlation with generic (|rs | = 0.02-0.27) and moderate correlation with dermatology-specific instruments (|rs | = 0.41-0.53). CONCLUSIONS: MF/SS have a significant impact on multiple domains of patients' QoL, including social, emotional and physical functioning. Current clinical measures do not adequately address QoL outcomes, underscoring the need for integrating formal disease-specific QoL assessment into the routine evaluation of MF/SS patients.

Metabolic interfaces between growth and reproduction. V. Pulsatile luteinizing hormone secretion is dependent on glucose availability.

To test the hypothesis that mechanisms controlling the secretion of LH are modulated by glucose availability, the acute effects of glucoprivation were studied. The model was the gonadectomized male lamb raised on a limited diet of artificial milk. The approach was to monitor LH secretion before and after the administration of a competitive antagonist of glucose metabolism, 2-deoxyglucose (2DG). We first determined whether LH secretion was influenced by glucose availability by administering 2DG at several doses. Peripheral administration of the glucose antagonist (240 and 480 mg/kg 2DG, single iv injection) transiently decreased LH pulse frequency, but not LH pulse amplitude. By contrast, LH secretion (frequency or amplitude) was not affected by lower doses (60 or 120 mg/kg) of the glucose antagonist. A second study was conducted to determine whether either the pituitary gland or the GnRH neurosecretory system per se is directly affected by short term glucoprivation. The competency of the pituitary was assessed by administering GnRH during the time when LH secretion is suppressed by pharmacological glucose blockade. Similarly, the function of the GnRH neurosecretory system was assessed by administering a GnRH secretagogue (N-methyl-D,L-aspartate) under the same glucoprivic conditions. In response to an optimized iv dose of 2DG, LH pulse frequency decreased. However, in lambs that received either GnRH or N-methyl-D,L-aspartate during the period of glucoprivation, LH pulse frequency was sustained at levels comparable to those before 2DG was given. To determine whether the effect of glucoprivation was central in origin, the glucose antagonist was administered into the lateral cerebral ventricle at 1/100th the doses used peripherally. Central administration of 2DG, independent of dose, transiently decreased LH pulse frequency, but not pulse amplitude. However, unlike the case with peripheral injection, plasma glucose values did not change after the administration of any dose of 2DG tested centrally. These findings indicate that glucose availability in the developing sheep influences LH secretion. Moreover, based upon analysis of LH pulse frequency, glucoprivation does not directly impair either the pituitary gland or the GnRH neurosecretory system. Collectively, these results suggest that glucose availability affects LH secretion by acting within the central nervous system at a detection site(s) peripheral to the GnRH neuron.

Central inhibition of gonadotropin-releasing hormone secretion in the growth-restricted hypogonadotropic female sheep.

Growth retardation induced by dietary restriction results in hypogonadotropism, and thus, puberty is delayed. The present studies determined 1) whether reduced LH secretion in the growth-retarded condition is due to a reduction in the frequency and/or in the amplitude of GnRH secretion, and 2) whether the mechanism regulating LH secretion is being actively inhibited via central mechanisms. To determine whether GnRH pulse frequency and/or amplitude are reduced during growth restriction, blood samples were simultaneously collected from pituitary portal blood for GnRH and from jugular blood for LH determinations over a 4-h period in ovariectomized lambs (52 wk of age) that were either growth restricted (28 kg; n = 8) or growing normally (60 kg; n = 7). As expected, the growth-restricted females were hypogonadotropic and exhibited a long LH interpulse interval compared with the normally growing females. However, although the GnRH interpulse interval was longer in the growth-restricted lambs compared with that in the normally growing lambs, the pattern of GnRH secretion did not directly correspond with that of LH secretion in the growth-restricted group. In addition, high amplitude GnRH pulses that coincided with LH pulses and small, low amplitude GnRH pulses without a concomitant LH pulse occurred. The second study tested the hypothesis that diet-induced hypogonadotropism is the result of actively inhibited central mechanisms by investigating the effects of the nonspecific central nervous system inhibitor, sodium pentobarbital, on pulsatile LH secretion in the growth-restricted lamb. Serial blood samples were collected from 11 ovariectomized lambs that were maintained at weaning weight (approximately 20 kg) by reduced diet. After a 4-h pretreatment period, six of the lambs were anesthetized with sodium pentobarbital for 4 h; the other five lambs were untreated and served as controls. Pentobarbital anesthesia reduced the LH interpulse interval (increased the frequency) and increased mean LH levels. These findings suggest that during growth restriction hypogonadotropism arises from a central inhibition of GnRH neurons and is manifest as a decrease in both frequency and amplitude of GnRH pulses.

Sexual differentiation of the surge mode of gonadotropin secretion: prenatal androgens abolish the gonadotropin-releasing hormone surge in the sheep.

In sheep, the surge mode of gonadotropin secretion is sexually differentiated, i.e. the LH surge is present in the female, but not in the male. The present study tested the hypothesis that sexual differentiation of the LH surge mechanism reflects a sex difference in the pattern of GnRH, and that prenatal androgens abolish the surge mode of GnRH secretion. We monitored the pattern of GnRH secretion in pituitary portal blood after acute treatment with estradiol in gonadectomized postpubertal males (n = 6), females (n = 6), and androgenized females (exposed prenatally to testosterone from day 30-90 in gestation, n = 7). Four capsules, each containing a 30-mm column of estradiol were implanted s.c. into each lamb to produce high physiologic concentrations of the hormone. Beginning 7 h later, portal and peripheral blood samples were collected hourly for 48 h for measurement of GnRH and LH, respectively. All females exhibited a GnRH surge beginning 13.0 +/- 0.4 h after estradiol treatment; this was accompanied by an LH surge. By contrast, only one male produced a small surge in GnRH (1.7 pg/min) with a latency of 32 h; a corresponding increase in LH occurred in this male. Likewise, among the androgenized females, only one exhibited GnRH and LH surges which began at about 22 h after estradiol treatment. Some of the androgenized females had sporadic increases in GnRH which were of lower amplitude than in the control females, and were unaccompanied by rises in LH. These findings provide the first direct evidence that the sex difference in the surge mode of LH secretion results from the sexual differentiation of the pattern of GnRH release. The study also suggests that androgens during prenatal development abolish the GnRH surge and subsequently, the generation of the LH surge.

Defeminization of the reproductive response to photoperiod occurs early in prenatal development in the sheep.

Photoperiod times the transition to sexual maturity in many seasonal breeders. In male and female sheep, photoperiod influences the timing of puberty differentially. Whereas in females, age at sexual maturity is highly dependent on photoperiod, puberty in males begins at the same age regardless of day length. We have determined that this sex difference is due to the organizing action of androgens during prenatal development. In the present investigation, we studied when during gestation (term: approximately 150 days) androgens defeminize the reproductive response to photoperiod. We compared the age at sexual maturity in female lambs treated with testosterone prenatally from Days 30 to 76 (Early, n = 7) or 89 to 135 (Late, n = 8) to that of normal males (n = 8) and normal females (n = 7). To reveal differential responsiveness to photoperiod, all lambs were maintained from birth under constant long days (16L:8D), a treatment that inhibits puberty in normal females. The age at the pubertal LH rise was determined in a standardized experimental model (lambs gonadectomized and treated with estradiol). As expected in the long day photoperiod, only 1 of 7 normal females had a pubertal rise in LH. In contrast, all males increased LH secretion by 6.7 +/- 0.6 wk. Similarly, in the Early group, a sustained increase in LH occurred in all females, but this was delayed relative to the increase in the males (16.8 +/- 1.7 wk; p < 0.001). The Late group had LH patterns similar to those of the normal females, with only 3 of 8 females having sustained elevations in LH. These data suggest that a "critical period" for the defeminization of the reproductive response to photoperiod occurs early in prenatal development. In addition, it appears that this critical period and the period for defeminization of the surge mode of gonadotropin secretion occur at similar stages in development. When challenged with an acute increase in estradiol, all normal and Late androgenized females responded with an LH surge. In contrast, none of the males and only 1 of 7 Early females produced a robust response to estradiol.

Prenatal androgens modify the reproductive response to photoperiod in the developing sheep.

In most seasonal breeders, photoperiod influences the timing of the transition to sexual maturity. In sheep, males and females express reproductive maturity under different photoperiods. Spring-born males begin the maturational process during lengthening days (spring), whereas females do so during shortening days (autumn). We hypothesized that photoperiod differentially influences the transition to sexual maturity in each sex, and that this difference results from the presence or absence of androgens prenatally. We monitored the timing of sexual maturity in male and female lambs (n = 8 each) and in prenatally masculinized female lambs (n = 7) maintained under controlled photoperiods (natural-simulate or reverse natural-simulate). Circulating LH was analyzed to reveal the timing of the pubertal gonadotropin rise; lambs were gonadectomized and implanted with estradiol to provide a constant feedback on LH secretion. Under natural-simulate photoperiod, LH increased in males at 7.0 +/- 0.3 wk when days were lengthening. In females treated similarly, sexual maturity occurred at 27.0 +/- 0.8 wk when day lengths were decreasing. The reverse photoperiod had no effect on males, but it delayed the expression of sexual maturity in females. Thus, LH also increased in males at 7.1 +/- 0.9 wk, while none of the females maintained under the same photoperiod had elevated LH secretion when the experiment was terminated (32 wk of age). Prenatal treatment with androgens masculinized the reproductive response to photoperiod; as in the males, LH increased in the androgenized females maintained under a reverse natural-simulate photoperiod at 7.1 +/- 0.4 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal testosterone differentially masculinizes tonic and surge modes of luteinizing hormone secretion in the developing sheep.

In sheep, prenatal exposure to androgens during a critical period for sexual differentiation can masculinize tonic luteinizing hormone (LH) secretion and defeminize the LH surge. The present study investigated the possible independent control of these two modes of LH secretion, as revealed by their developmental history. Specifically, we tested the hypothesis that separate critical periods exist for androgenization of tonic and surge LH secretion. Pregnant ewes were treated weekly with testosterone cypionate (200 mg in oil). As a control and to induce robust masculinization of reproductive neuroendocrine function, one group of females received testosterone from day 30 to 86 of gestation (LONG group). To determine if masculinization of tonic LH secretion develops separately from that of the LH surge, two additional groups were treated from day 30 to 51 (EARLY group) or 65-86 (LATE group). At birth, the external genitalia of the LONG- and EARLY-treated females were masculinized; those of the LATE-treated group were normal. At 2 weeks of age, all androgenized females, together with normal males and females (n = 8 each), were gonadectomized and steroids replaced using an estradiol-filled Silastic capsule. First, to determine the timing of the pubertal decrease in steroid sensitivity, circulating LH was monitored twice weekly. Second, to test the function of the LH surge system, LH was measured every 1-2 h for 60 h after an acute increase in estradiol at 9 months of age. With regard to tonic LH secretion, in control males and LONG-treated females, a sustained increase in tonic LH in the presence of constant steroid feedback occurred at 7.1 +/- 0.3 and 10.9 +/- 1.7 weeks of age, respectively (mean +/- SE). In control females, tonic LH increased at 27.1 +/- 0.8 weeks. Despite the differences in their genitalia, EARLY and LATE testosterone treatment produced intermediate effects: LH secretion increased at 19.3 +/- 1.2 and 20.4 +/- 0.8 weeks, respectively. In response to acute estradiol stimulation, all control females produced a surge of LH that peaked 18.4 +/- 0.6 h after steroid treatment. For the control males and LONG-treated females, LH concentrations were not sustained above unsuppressed pretreatment levels throughout the 60-hour sampling period. All but 4 of the 18 EARLY- and LATE-treated females responded to estradiol stimulation with a surge of LH that peaked at 29.8 +/- 1.6 and 31.8 +/- 1.3 h, significantly later than that of control females.(ABSTRACT TRUNCATED AT 400 WORDS)

Prenatal photoperiod and the timing of puberty in the female lamb.

In female sheep, photoperiod regulates the timing of the transition to adulthood. We tested the hypothesis that photoperiod very early in development influences the timing of the pubertal LH rise that initiates sexual maturation. The first experiment was designed to determine the influence of day length information perceived before birth by varying prenatal photoperiod experience. Two groups that experienced either increasing or constant long days prenatally, and then a gradually decreasing photoperiod postnatally, reached puberty at the same age (Prenatal Increase, 20.4 +/- 0.5 wk vs. Prenatal Long Days [LD], 19.4 +/- 0.8 wk). Puberty in these groups was much earlier than in two control groups exposed to the same photoperiods, but beginning at birth, for 13 wk (Postnatal Increase, 29.6 +/- 1.0 wk; Postnatal LD, 26.2 +/- 1.3 wk). In the second experiment, the role of prenatal photoperiod in timing sexual maturity was also examined through the use of treatments with greater contrast. Lambs were exposed prenatally to either decreasing or increasing day lengths. Beginning at birth, both groups were exposed to a decreasing photoperiod. Although only half of the lambs in each group exhibited the pubertal LH rise, those that attained puberty did so at the same age (Prenatal Decrease, 14.8 +/- 1.0 wk vs. Prenatal Increase, 14.8 +/- 0.3 wk). We therefore conclude that day length cues experienced postnatally predominantly time sexual maturation in the female lamb.

Hypothalamic versus pituitary stimulation of luteinizing hormone secretion in the prepubertal female lamb.

Glutamate and aspartate have been hypothesized to function as neurotransmitters in the regulation of the gonadotropin-releasing hormone (GnRH) neurosecretory system. We, therefore, determined if hypothalamic stimulation of luteinizing hormone (LH) secretion in the intact prepubertal female lamb could be achieved by intravenous injection of N-methyl-D,L-aspartate (NMA), a glutamate agonist. A pilot study determined a dose of NMA that would induce physiologic pulses of LH (GnRH). Subsequently, we compared the ability of NMA with exogenous GnRH to induce ovulation in the prepubertal lamb when administered chronically. Eighteen prepubertal lambs (21 weeks of age, 34.2 +/- 1.5 kg body weight) were treated intravenously with either NMA (2 mg/kg, n = 6) or GnRH (68 ng/injection or approximately 2 ng/kg, n = 6) for 3 days, every 2 h on day 1 and every 1 h on days 2 and 3, or received no treatment (controls, n = 6). Gonadotropin surges were detected only in GnRH-treated lambs (5/6 lambs, onset = 54.0 +/- 4.5 h from the start of study, mean +/- SE). Compared to 83% of GnRH injections inducing LH pulses, only 47% of NMA injections induced LH pulses. Because each injection of NMA did not induce a pulse of LH, a second experiment was performed in an attempt to optimize the LH response to NMA. Ten prepubertal lambs (25 weeks of age) were injected every 2 h for 24 h with higher doses of NMA, either 4 mg/kg (n = 5) or 16 mg/kg (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)